Handbook of Solvents - George Wypych - ChemTech - Ventech!

20.8 Solvents and the liver 1397
the induction of cytochrome p-450 enzymes leading to greater formation of toxic intermediates.
34 In contrast, exposure to ethanol immediately preceding carbon tetrachloride exposure
leads to competitive inhibition of carbon tetrachloride metabolism. 34 Several other
alcohols (e.g., isopropanol, 32,35 t-butyl alcohol 36 ) and ketones 37 potentiate the effect of carbon
tetrachloride hepatotoxicity. Exposures to other haloalkanes 38 or haloalkenes 39 potentiate
carbon tetrachloride hepatotoxicity while carbon disulfide exposure is ‘protective’ of
carbon tetrachloride hepatototoxicity. 40 Dietary factors, medications, chronic diseases and
persistent halogenated environmental contaminants such as PCB’s and DDT have been
shown to modulate or exacerbate the hepatotoxicity of carbon tetrachloride. 5,21
Cellular disruption leading to hepatocellular necrosis results from damage to cellular
macromolecules by trichloromethyl radicals. 24 Cellular disruption involves alteration of
calcium homeostasis, 41 impaired oxidative phosphorylation, 42 and trichloromethyl radical
binding to cellular proteins, nucleic acids, and induction of lipid peroxidation. 6,21
Histologically there is preferential necrosis of zone three hepatocytes in the liver acinus so
called centrizonal necrosis as well as zone three steatosis.
As with other halogenated hydrocarbons, carbon tetrachloride is an intrinsic
hepatotoxin with adverse effects occurring at predictable exposure levels. The American
Conference of Governmental and Industrial Hygienists (ACGIH) Threshold Limit Value
(TLV), for carbon tetrachloride, based upon animal and human exposure data where limited
adverse health effects are observed, is 5 ppm over an 8 hour time weighted average and a 40
hour work week for carbon tetrachloride. 43 In human population studies, elevations in
hepatic transaminase levels occur at carbon tetrachloride concentrations averaging 200
ppm, with small but significant elevations of ALT, AST, Alk Phos and GGT occurring at
exposure levels below the TLV. 44-46
Carbon tetrachloride also affects many other organ systems, specifically the central
nervous system, the gastrointestinal tract, the liver and the kidney. 5,6 Hepatic manifestations
of carbon tetrachloride include serum AST and ALT elevations as early as three hours
following exposure. Clinical evidence of hepatic disease occurs approximately twenty four
hours following exposure, and is manifest in half the cases as jaundice accompanied by
hepatic enlargement. In severe poisonings, progressive hepatic injury leads to coma and
death within a week of exposure. Fortunately, non lethal exposures are often associated with
significant clinical recovery in two to three weeks. Treatment is limited to supportive care,
in a hospital setting. Chronic exposures to carbon tetrachloride have been associated with
hepatic fibrosis and cirrhosis in animals and documented as well in several case reports in
humans. 47-50
20.8.2.3 Chloroform
Medical and industrial use of chloroform has also declined significantly. 51 Today, industrial
use is limited to the manufacture of refrigerants and fluoropolymers. 51 Chloroform metabolism
involves the same cytochrome p-450 2E1 as carbon tetrachloride but with oxidation of
chloroform to trichloromethanol with spontaneous formation of phosgene via the elimination
of hydrochloric acid. 3 In turn, phosgene reacts with hepatic lipids and microsomal proteins
and depletes cellular glutathione, a cellular antioxidant. 7,51 Factors potentiating
chloroform hepatotoxicity include ethanol and other alcoho1s, 52-54 hypoxia, 53 ketones, 55
fasting state, 56,57 concomitant chronic medical disease and chronic medication use, or those
with repeated exposures to chloroform. 5 The pattern of human liver injury associated from
chloroform poisoning is centrilobular necrosis and steatosis. 23